An understanding of the mechanisms of IgE synthesis is essential for devising rational therapeutic interventions in allergy. Two signals are required for the induction of IgE synthesis in human B cells. The first signal is delivered by IL4 and results in the induction of epsilon germ- line transcription but not in IgE synthesis. The second signal is a B cell activation signal which can be delivered by T cells and by EBV virus but not by classical B cell activators. B cell activation by T cells or EBV are not suitable models to dissect the signals required for IgE synthesis. We have recently reported that Mab to the B cell antigen CD40 synergizes with IL4 to induce IgE synthesis in highly purified B cells. CD40 is likely to play a role in the physiologic regulation of IgE because recombinant soluble CD40 inhibits T cell driven IL4 dependent IgE synthesis. We propose to study the mechanisms of induction of IgE synthesis by anti-CD40 + IL4 and to use this model to study IgE regulation.
Our aims are to: 1) Study the characteristics of the B cell responding to anti-CD40 + IL4 as to a) activation state, b) surface phenotype, c) frequency. 2) Examine S mu -> S epsilon switching in B cells stimulated with anti- CD40 + IL4 by a) PCR analysis of switch recombination, b) sequencing the Smu -> S epsilon junction, c) determining the role of the CD40 signal in switch recombination. 3) Examine the modulation of IgE synthesis in B cells by receptor crosstalk, cytokines nd mediators of allergy. 4) Study the role of CD40 in T cell driven IgE synthesis by examining a) the role of CD40 in IgE synthesis induced by cognate vs. noncognate T-B cell interactions, b) surface expression of the putative CD40 ligand by T cells. The proposed studies should enhance our understanding of the IgE response and are relevant to the study of switching to isotypes other than IgE as well as to study of potential switch defects in patients with antibody deficiency syndromes.
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